One of the major determinants of reinstatement of cocaine use among human addicts is acute re-exposure to the drug, which often precipitates cocaine craving and relapse. This grant proposal will use an animal model of cocaine relapse in order to determine the anatomical and pharmacological determinants of the reinstatement of cocaine seeking. Specifically, these aims will systematically analyze ionotropic glutamate receptors in the core and shell subregions of the nucleus accumbens and their respective roles in reinstatement. Specific Aim 1 will assess the ability of intra-accumbal core or shell AMPA to reinstate cocaine-seeking. We will then determine the influence intra-accumbal core or shell microinjection of an AMPA receptor antagonist has on the reinstatement of cocaine priming-induced drug seeking. Specific Aim 2 will methodically analyze the effects of NMDA agonists and antagonists administered into either the core or the shell of the nucleus accumbens on the reinstatement of cocaine-seeking. It is possible that reinstatement induced by intra-accumbal AMPA, NMDA, or an NMDA antagonist could be dopamine-dependent, a hypothesis that will be addressed in Specific Aim 3.